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Open Access Full Text Article ORIGINAL RESEARCH Ripasudil Endgame: Role of Rho-Kinase Inhibitor as a Last-Ditch-Stand Towards Maximally Tolerated Medical Therapy to a Patient of Advanced

Mayuresh Naik 1 Purpose: To elucidate the use of Ripasudil in patients of advanced glaucoma on maximally Monika Kapur2 tolerated medical therapy who could not be offered the option of surgery due to the global VishnuSwarup Gupta1 pandemic lockdown. HarinderSingh Sethi3 Materials and Methods: Only patients with primary open angle glaucoma (POAG), who Kartikeya Srivastava3 had a cup-disc ratio (CDR) of 0.9 or a near total cupping on maximum tolerated medical therapy for at least 4 weeks and yet could not meet the target IOP were included. Target IOP 1 Department of Ophthalmology, H.I.M.S.R was defined as ≤12 mm Hg. A total of 30 patients were enrolled. All patients in study cohort & H.A.H. Centenary Hospital, New Delhi, India; 2Department of Ophthalmology, were started on E/D Ripasudil BD. Patients were followed up at 1 week, 2 weeks, 4 weeks School of Medical Sciences & Research, and then monthly for 6 months for their best corrected visual acuity (BCVA), intraocular Sharda University, Greater Noid, Uttar pressure (IOP), disc changes (slit lamp biomicroscopy), perimetry, and retinal nerve fibre Pradesh, India; 3Department of Ophthalmology, V.M.M.C & Safdarjung layer analysis using optical coherence tomography (OCT-RNFL). Hospital, New Delhi, 110029, India Results: Mean pre-treatment IOP on five drugs was 18.3 ± 2.1 mm Hg (range 14to 22mmHg) on maximally tolerated medical therapy. At 1 week follow-up, mean post- treatment IOP was 15.1 ± 1.7 mm Hg (range 12 to 18mmHg) and at 2 week follow-up, mean post-treatment IOP was 12.5 ± 1.9 mmHg (range 10 to 16mmHg). Thus, target IOP ≤12mmHg was attained in 28 patients at 2 weeks. This target IOP was maintained throughout the 6 months of follow-up period. Of the 2 patients who could not meet target IOP, 1 patient needed rearrangement of their fixed-drug-combinations to achieve target IOP at 4 weeks. The second patient required unfixing of all fixed-drug-combinations to achieve target IOP at maximally tolerated medical therapy at 6 weeks. Conclusion: Ripasudil not only provides a better IOP control but also has a high safety profile even when started as an add-on drug to already-existing yet inadequate maximally tolerated medical therapy. Keywords: advanced glaucoma, ripausdil, ROCK1 inhibitor, maximally-tolerated-medical- therapy, COVID-19 lockdown

Introduction As of 2020, glaucoma is the most important cause of irreversible vision loss Correspondence: Mayuresh Naik 1 Department of Ophthalmology, H.I.M.S.R globally. Based on prevalence studies, it is estimated that 79.6 million individuals & H.A.H. Centenary Hospital, Room will have glaucoma in 2021. Of these, it is estimated that more than 11 million No. 3 of Eye OPD, 1st Floor of OPD Building, Near GK-2, Alaknanda, New individuals will be bilaterally blind due to glaucoma in 2021 (around 13% of the Delhi, 110062, India cases).2 At least 50% of those with glaucoma are unaware that they are affected. In Tel +91-8287344576 Email [email protected] some developing countries, 90% of glaucoma is undetected and thus nearly one

Clinical Ophthalmology 2021:15 2683–2692 2683 © 2021 Naik et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Naik et al Dovepress fifth of the patients become blind in either or both eyes.3 Centenary Hospital, New Delhi. All procedures performed (IOP) is the single most important in our study involving human participants were in accor­ modifiable risk factor for efficient glaucoma control. dance with the 1964 Helsinki Declaration and its later Conventionally, the initial standard of care for primary amendments. open angle glaucoma is medical with surgical options This retrospective, observational study was conducted on being reserved for instances when there is documented patients visiting Speciality Glaucoma Clinic at Tertiary health­ structural or functional progression despite adequate IOP care hospital, ie H.I.M.S.R & H.A.H. Centenary Hospital, control or inability to control IOP on medical Department of Ophthalmology from 1 March 2020 to 30 management. November 2020. Advanced glaucoma, defined as near total cupping with or without severe visual field (VF) loss within 10 degree of Inclusion Criteria fixation, tends to have a worse visual and overall Only patients with primary open angle glaucoma were prognosis.4 Lowering the intraocular pressure (IOP) to selected. the lower teens as well as reducing IOP fluctuations has All patients who had cup-disc ratio (CDR) of 0.9 or the strongest evidence of protecting the optic nerve and a near total cupping and/or a mean deviation of −12dB preserving the remnant VF.5,6 The conventional treatment (Hodapp-Anderson-Parrish criteria) on the standard protocol dictating the use of anti-glaucoma medications till Humphrey Visual Field 24–2 program (Carl Zeiss maximally tolerated medical therapy before the surgical Meditec)9 despite aggressive maximum tolerated medical intervention, does not apply to the advanced glaucoma therapy for IOP control including a analo­ stages. Recent guidelines from National Institute of gue, α-agonist, β-blocker, carbonic anhydrase inhibitor, Health and Clinical Excellence of UK as well as the cholinergic agonist for at least 4 weeks and yet could not American Glaucoma Society (AGS) recommend primary meet the target IOP were included. Target IOP (main out­ glaucoma surgery in such cases.7 However, with the come measure) was defined as ≤ 12 mm Hg. advent of the COVID-19 pandemic and the resultant lock­ A total of 30 patients were enrolled. down starting March 2020, elective surgeries and proce­ dures were halted and indefinitely deferred until it was Exclusion Criteria safe for both the health care workers and the patients. In Patients with history of any previous surgery, uveitis, such a scenario, there was no option but to resort to ocular infection, having hypersensitivity to Ripasudil, on alternative strategies including modifying fixed-drug- any immunosuppressive therapy (topical/systemic), with combinations within the tenets of previously existing history of herpetic keratitis and contact lens wearers maximally tolerated medical therapy. Ripasudil was FDA were excluded from the study. approved for the treatment of glaucoma in 2014 but the Patients who were not on maximally tolerated medical use was limited to Japan and Korea(PMDA) since then. therapy as elaborated above or those who could attain and However, the recent advent of its availability in India maintain their target IOP on maximally tolerated medical ushered in a new arena of opportunity that could be har­ therapy were excluded from the study. nessed for lowering IOP via a new pathway, ie the selec­ tive Rho-associated coiled-coil-containing protein kinase 1 Procedure and Data Collection (ROCK1) inhibition. All patients in study cohort were started on E/D Our study attempted to elucidate the use of Ripasudil Ripasudil BD. in patients of advanced glaucoma on maximally tolerated Patients were followed up at 1 week, 2 weeks, 4 weeks medical therapy who could not be offered the option of and then monthly for 6 months. surgery due to the global pandemic lockdown. The parameters evaluated were: Best corrected visual acuity (BCVA), intraocular pres­ Materials and Methods sure (IOP) using Goldmann’s Applanation tonometry, disc Written and informed consent was taken from all patients. changes (slit lamp biomicroscopy using 90-D lens), perime­ This study was approved by the Institutional Ethics try for visual field progression (Humphrey Visual Fields Committee and Institutional Review Board (IEC.IRB/ ©Carl Zeiss Meditec), and retinal nerve fibre layer analysis HIMSR/HAHCH/03/2020-17) of H.I.M.S.R & H.A.H. using Optical Coherence Tomography (OCT-RNFL using

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Cirrus™ HD-OCT© Carl Zeiss Meditec). Structural The second patient required unfixing of all fixed-drug- changes were identified by slit lamp biomicroscopy and combinations to achieve target IOP at maximally tolerated staged using disc damage likelihood scale (DDLS).8 medical therapyat 6 weeks. No drugs were changed, sub­ Categorical variables were presented in number and stituted or modified during the 6 months of the follow-up percentage (%) and continuous variables were presented period. as mean ± SD. Quantitative variables were compared using paired t-test was used for comparison between pre Disc Changes and post. Qualitative variables were compared using Chi- Structural changes were identified by slit lamp biomicro­ Square test/Fisher’s Exact test. A p-value of <0.05 was scopy and staged using disc damage likelihood scale considered statistically significant. The data was entered in (DDLS). No structural deterioration was noted in MS EXCEL spreadsheet and analysis was done using a follow up period of 6 months. Statistical Package for Social Sciences (SPSS) ver­ sion 21.0. Field Changes Results Pre-treatment all patients had visual fields with grossly Demographic Data depressed total deviation plots. Mean of mean deviation (MD) plot was −26.78 ± 13.76dB (Figures 2 and 3). Out of the 30 patients, 28 patients were ≥ 55 years of age Visual fields showed bi-arcuate scotoma in 12 of the (mean 63.8 yrs). Eighteen of the patients were males, and patients with sparing of a central and temporal island of 12 were females. There was no racial disparity. None of the patients underwent any previous surgery (Table 1). vision without a macular splitting on 10–2 field charting while 5 patients had bi-arcuate scotoma with annular Best Corrected Visual Acuity vision as well as a macular split on 10–2 field charting. Inferior arcuate scotomas were seen in 5 patients and Pre-treatment Snellen’s BCVA was > 6/12 in 22 patients superior arcuate scotomas were seen in 5 patients. Three and 6/60–6/12 in 8 patients. patients had a severely depressed fields with macular split At follow-up, the BCVA remained stable in 28 patients. on 10–2 visual field. It dropped by 1 Snellen line in 2 patients and 2 Snellen lines Deepened or enlarged defect was defined as worsening in 2 patients over a period of 6 months and later improved of two or more points within,adjacent or contiguous to the to 6/6P following uneventful phacoemulsification. existing scotoma by more than 10 dB. There was no defined progression in any of the 30 patients; however, Intraocular Pressure (IOP) mean deviation (MD) was found to be increased in 4 Figure 1 patients which improved substantially following cataract Mean pre-treatment IOP on five drugs was 18.3 ± surgery. 2.1 mm Hg (range 14 to 22 mmHg) on maximally toler­ ated medical therapy (Figure 1). At 1 week follow-up, mean post-treatment IOP was OCT-RNFL 15.1 ± 1.7 mm Hg (range 12 to 18 mmHg) and at 2 week The OCT-RNFL was employed at the following instances: follow-up, mean post-treatment IOP was 12.5 ± 1.9 mmHg i. At enrolment as a baseline OCT-RNFL for further (range 10 to 16 mmHg). reference Thus target IOP ≤ 12 mmHg was attained in 28 ii. After target IOP was achieved and slit-lamp biomi­ patients at 2 weeks and was maintained throughout the 6 croscopy did not show any further structural deterioration months of follow-up period. The mean post-treatment IOP and perimetry did not show any further functional dete­ at 6 months was 10.4 ± 1.3 mmHg (range 9 to 12 mmHg). rioration, so as to pick up the earliest instances of micro­ This represented a statistically significant reduction in IOP scopic nerve loss/damage. (p<0.05) as compared to the pre-treatment IOP. The OCT-RNFL was outside normal limits in all Of the 2 patients who could not meet target IOP, 1 patients of the cohort but did not show any statistically patient needed rearrangement of their fixed-drug- significant documented progression of further nerve loss as combinations to achieve target IOP at 4 weeks. compared to the baseline OCT-RNFL done at baseline.

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Table 1 Demographic Data at Baseline Showing the Mean Deviation in HVF 30–2 and the Fixed-Drug-Dose-Combinations in the Study Population

Patient Age/Sex BCVA at MD in HVF 30–2 at Fixed-Drug Dose Combination (FDDC) Used by Patient No. M = Male Baseline Baseline (in dB) F = Female (R)(L)

1. 67/M (6/6P)(6/6P) −24.32 ( + )( + )()

2. 56/M (6/9P)(6/9P) −27.89 ( + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

3. 52/M (6/6)(6/6) −26.28 ( + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

4. 72/F (6/12)(6/12) −23.54 (Latanoprost)()(Brominidine + Timolol)(Pilocarpine)

5. 59/F (6/18)(6/18P) −25.67 (Travoprost + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

6. 63/M (6/24P)(6/24) −31.90 (Travoprost + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

7. 79/M (6/12)(6/12) −30.32 (Bimatoprost)(Brimonidine)(Brinzolamide + Timolol)(Pilocarpine)

8. 71/F (6/36)(6/36) −34.67 (Travoprost)(Brinzolamide)(Brimonidine + Timolol)(Pilocarpine)

9. 68/F (6/9)(6/9) −21.66 (Bimatoprost + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

10. 71/F (6/60)(6/36P) −35.40 (Travoprost)(Dorzolamide)(Brimonidine + Timolol)(Pilocarpine)

11. 57/M (6/9P)(6/12) −24.54 (Bmatoprost + Timolol)(Dorzolamide)(Brimonidine)(Pilocarpine)

12. 58/M (6/6)(6/6) −29.12 (Latanoprost + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

13. 51/M (6/6)(6/6) −18.16 (Bimatoprost + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

14. 55/F (6/9P)(6/9P) −29.38 (Travoprost + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

15. 62/M (6/6P)(6/9) −27.30 (Latanoprost)(Dorzolamide)(Brominidine + Timolol)(Pilocarpine)

16. 64/F (6/9)(6/9) −24.18 (Travoprost + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

17. 61/M (6/12)(6/12) −29.02 (Travoprost + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

18. 61/M (6/9)(6/9) −23.15 (Bimatoprost)(Brimonidine)(Brinzolamide + Timolol)(Pilocarpine)

19. 68/M (6/24)(6/24) −31.34 (Travoprost)(Brinzolamide)(Brimonidine + Timolol)(Pilocarpine)

20. 70/M (6/36)(6/36) −36.90 (Bimatoprost + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

21. 65/M (6/6P)(6/6P) −22.30 (Travoprost)(Dorzolamide)(Brimonidine + Timolol)(Pilocarpine)

22. 68/F (6/18P)(6/24) −30.41 (Bmatoprost + Timolol)(Dorzolamide)(Brimonidine)(Pilocarpine)

23. 70/F (6/60)(6/36P) −38.21 (Latanoprost + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

24. 60/M (6/9)(6/9) −18.89 (Bimatoprost + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

25. 61/F (6/6)(6/6) −16.66 (Travoprost + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

26. 63/M (6/9)(6/9) −19.84 (Latanoprost)(Dorzolamide)(Brominidine + Timolol)(Pilocarpine)

27. 74/M (6/24P)(6/36) −33.72 (Travoprost + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

28. 71/F (6/24)(6/18P) −35.59 (Travoprost + Timolol)(Brimonidine + Brinzolamide)(Pilocarpine)

29. 58/M (6/6)(6/6) −15.35 (Bimatoprost)(Brimonidine)(Brinzolamide + Timolol)(Pilocarpine)

30. 61/F (6/9)(6/6P) −17.90 (Travoprost)(Brinzolamide)(Brimonidine + Timolol)(Pilocarpine)

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MEAN IOP AT EACH FOLLOW-UP VISIT 20

18

16

14

12

10

8

6

4

2

0 IOP IOP AT 1 IOP AT 2 IOP AT 4 IOP AT 2 IOP AT 3 IOP AT 4 IOP AT 5 IOP AT 6 BASELINE WEEK WEEKS WEEKS MONTHS MONTHS MONTHS MONTHS MONTHS

Figure 1 Graphical representation of the Mean IOP at each patient visit in the study population.

Figure 2 Humphrey’s visual field analyser charts of a patient with cup-disc ratio 0.9 showing generalized depression in 30–2 visual field charting and absence of macular splitting in 10–2 visual field charting in left eye.

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Figure 3 Humphrey’s visual field analyser charts of a patient with cup-disc ratio 0.9 showing a biarcuate scotoma in 30–2 visual field charting in left eye.

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Adverse Effect Profile Advanced glaucoma patients need a multifactorial Conjunctival hyperemia was seen in 4 patients, and it was approach wherein the vision and overall function of the mild to moderate for the initial two hours following instil­ patient is considered before a decision is reached regarding lation and resolved thereafter. the preferred mode of therapy, be it medical, laser or surgical. Since a randomised clinical trial comparing the outcomes of all three modes of treatment in advanced Discussion glaucoma patients is lacking, there is no uniformly, uni­ Glaucoma is the third leading cause of visual disability in versally accepted best treatment option for these group of the world.2 Approximately 20.9% of patients with POAG patients. Recently, National Institute for Health and were blind in either or both eyes, in the Aravind Clinical Excellence guideline of UK has suggested pri­ 10 Comprehensive Eye Study. There is a lack of consensus mary glaucoma surgery for patients presenting with on the definition of advanced glaucoma. According to the advanced glaucoma13 while a study conducted by King 9 classic Hodapp-Anderson-Parrish textbook, patients with et al argued that the current evidence is not supportive of a mean deviation of −12dB on the standard Humphrey this recommendation.14 Burr J. et al compared medical Visual Field 24–2 program (Carl Zeiss Meditec) have versus surgical interventions for POAG and concluded advanced glaucoma. The International classification of that there is insufficient evidence to suggest that the effi­ Diseases 9 (365.73) and 10 (7th digit “3”) diagnostic cacy and cost-effectiveness of surgery was superior as code defines severe stage (or advanced stage or end stage compared to recently available medications in patients of glaucoma) as optic nerve abnormalities consistent with advanced glaucoma.15 glaucoma and glaucomatous visual field abnormalities in Amongst the newer glaucoma medications, Ripasudil both the hemifields and/or loss within 5º of fixation in at has shown the most promising results. Ripasudil hydro­ least one hemifield. We included patients with 0.9 or near chloride hydrate is the world’s first Rho-associated coiled- total cupping with visual field defects encroaching or coil-containing protein-kinase (ROCK) inhibitor that lowers sparing the central 10º of fixation, as these are the patients IOP by increasing the conventional aqueous outflow with worst prognosis and in need of aggressive glaucoma through the and Schlemm’s canal by control with intensive treatment. decreasing outflow resistance. Ripasudil induces basic cel­ Advanced glaucoma at presentation is a major risk lular changes such as cell contraction, cell motility, cytos­ 11 factor for lifetime blindness. These patients are at immi­ keleton rearrangement, cell adhesion and remodelling of nent danger of losing the remnant vision with an overall cell to cell contact in the Trabecular meshwork- worse prognosis and in desperate need of aggressive glau­ Schlemm's canal pathway. Another important aspect is coma management. Glaucoma progression is attributable that Rho-kinase inhibitors can potentially alter episcleral not only to persistent IOP elevation but also to short and venous pressure which can bring down the IOP further long term IOP fluctuations. At least 40% IOP reduction is given that the episcleral venous pressure acts as required to prevent progression in advanced glaucoma a maximum under which it is difficult to bring IOP down. cases. In the Advanced Glaucoma Intervention Study The IOP lowering efficacy of Ripasudil has been well (AGIS) patients that did not show any progression had investigated in patients of POAG and OHT. In various a mean IOP of 12 mm Hg.12 Also, in patients with studies, Ripasudil has demonstrated efficacy in lowering advanced glaucoma showing functional or structural pro­ the IOP when used as monotherapy or in combination gression in spite of achievement of target IOP, assessment with beta-blockers or prostaglandin analogues. According and control of peak diurnal IOP and IOP fluctuations to a study carried out in Japanese patients, who were on 2- should be given equal importance as absolute reduction or 3-drug medical therapy, IOP decreased from 2.6 mm Hg of IOP. Hence the management of advanced glaucoma is to 3.1mm Hg, ie approximately 20% to 30% IOP reduction targeted towards maximally tolerated medical therapy from baseline after administration of Ripasudil.12 initiated as soon as possible so that the need of surgery Our cohort study included 30 patients with diagnosed can be assessed and prognosticated to the patient. advanced glaucoma, who had been receiving maximally In our study, we included patients with near-total optic tolerated medical therapy for a long period of time but disc cupping with severe visual field loss within 10 failed to achieve the target IOP. These patients were degrees of fixation, ie scotoma on or encroaching fixation. advised Trabeculectomy with Mitomycin C and were

Clinical Ophthalmology 2021:15 https://doi.org/10.2147/OPTH.S318897 2689 DovePress Naik et al Dovepress supposed to undergo the same, but elective operative pro­ Despite the noteworthy ophthalmic impact of our study, cedures were indefinitely deferred post the advent of there are a few limitations. Firstly, the size of the cohort was COVID-19. The recent availability of Ripasudil in the small and there was no parallel control group for compar­ Indian market provided temporary respite as our study ison. Secondly, for patients of advanced glaucoma who are demonstrated statistically significant IOP lowering effects already on five drugs, adding a 6th drug to the medical of Ripasudil when used as an adjunctive therapy to exist­ armamentarium for a lifetime raises concerns regarding ing maximal medical therapy in patients of advanced compliance considering the socio-economic status in glaucoma. Ripasudil was clearly a better alternative to a developing country like India. Even in developed coun­ oral therapy like Tab. Diamox ( ©Alembic tries, a joint discussion between the glaucoma specialist and Pharmaceuticals) especially in a situation like COVID-19 the patient would/may/might tend towards glaucoma surgery because Diamox would have required monitoring of renal as against the trial of adding a 6th drug in our efforts to function which would have been difficult to do when our achieve target IOP on maximally tolerated medical therapy. prime intention was to reduce the number of hospital The only possible counter-argument to this would be an visits. objective assessment of the costs involved: a 5mL vial of The mean IOP reduction from baseline was 17.4% E/D Ripatec (Ripasudil 0/4% w/v © Ajanta Pharma Ltd) after 1 week and 31.6% after 2 weeks of starting costs Rs. 262 which is just about equivalent of 3$ and is Ripasudil and the predefined target IOP was achieved in nowhere comparable to the cost of surgery. Surgery provides an edge over socioeconomic issues all 30 patients. Thus, the adjunctive therapy with and adherence, with the benefit of strict IOP control and Ripasudil may be effective in deferring surgery at least little diurnal variations. This is important in Indian setup for short term as all of the patients achieved the predefined where nearly 35% of the population falls below the inter­ target IOP. This target IOP was maintained during the 6 national poverty line. However, in the scenario that sur­ months of the study period. This additive IOP lowering gery is precluded (eg a global pandemic in this case) for effect of Ripasudil is attributable to the fact that its advanced glaucoma patients with poor IOP control and/or mechanism of action differs from that of other antiglau­ at risk of glaucoma progression, addition of Ripasudil is coma medications and can be explained by two a brilliant add-on to previously existing maximally toler­ hypothesis.15–19 Firstly, Ripasudil not only induces con­ ated medical therapy in order to achieve target IOP at least traction and rounding of cell bodies in the trabecular in the immediate short-term timeline. meshwork but also decreases transendothelial resistance, thus increasing transendothelial flux. Secondly, it is sup­ Conclusion posed that it takes a few weeks for intraocular distribution Despite the paradigm shifts that have been proposed in the of Ripasudil to stabilise and thus it takes time for management of advanced glaucoma, Ripasudil not only Ripasudil to decrease the extracellular matrix accumula­ provides a better IOP control but also has a high safety tion and eventually increase the conventional aqueous profile even when started as an add-on drug to already- outflow. existing yet inadequate maximally tolerated medical ther­ The safety profile of Ripasudil is superior to prostaglan­ apy. Since it can also serve as a cost effective addition to din analogues and other antiglaucoma medications as seen in medical armamentarium of glaucoma, it has literally been various studies. The most common adverse effect with the last ditch stand to preserve salvageable vision in Ripasudil was conjunctival hyperemia, blepharitis and aller­ patients of advanced glaucoma during the COVID-19 16–19 gic conjunctivitis. Regarding the safety profile of pandemic. Ripasudil in our study, conjunctival hyperemia was seen in 4 patients, and it was mild to moderate for the initial two Statement of Justification hours following instillation and resolved thereafter. This The following case series represents a retrospective analy­ hyperemia is hypothesized to be caused by the relaxation sis of the safety and efficacy of Ripasudil in cases of of vascular smooth muscles as Ripasudil is known to be advanced glaucoma in order to deduce whether the Rho- a vasodilator. There was no incidence of blepharitis neither kinase inhibitor can be of any value in our pursuit of any allergic conjunctivitis nor any other adverse effect buying time to preserve salvageable vision in patients of reported during the 6 month follow-up period. advanced glaucoma.

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Ethical Clearance 6. Caprioli J, Coleman AL. Intraocular pressure fluctuation a risk factor for visual field progression at low intraocular pressures in the Obtained from Ethical Clearance Committee, Institution advanced glaucoma intervention study. Ophthalmology. 2008;115 Review Board. (IEC.IRB/HIMSR/HAHCH/03/2020-17). (1123–1129):e3. doi:10.1016/j.ophtha.2007.10.031 7. National Institute for Health and Clinical Excellence (NICE). Glaucoma: Diagnosis and Management of Chronic Open Angle Ethical Standards Glaucoma and . Clinical Guidelines CG85, All procedures performed in studies involving human par­ UK National Institute for Health and Clinical Excellence (NICE) Guidelines. Developed by the National Collaborating Centre for ticipants were in accordance with the ethical standards of Acute Care; 2009. the institutional and/or national research committee and 8. Henderer JD. Disc damage likelihood scale. Br J Ophthalmol. 2006;90(4):395–396. doi:10.1136/bjo.2005.083360 with the 1964 Helsinki Declaration and its later amend­ 9. Hoddapp E, Parrish RK II, Anderson DR. Clinical Decisions in ments or comparable ethical standards. Glaucoma. Mosby, St. Louis Advanced Glaucoma Intervention Study. 1993. 10. Ramakrishnan R, Nirmalan PK, Krishandas R, et al. Glaucoma in Informed Consent a rural population of southern India: the Aravind comprehensive eye survey. Ophthalmology. 2003;110(8):1484–1490. doi:10.1016/S0161- Informed consent was obtained from all individual parti­ 6420(03)00564-5 cipants included in the study. 11. Peters D, Bengtsson B, Heijl A. Factors associated with lifetime risk of open-angle glaucoma blindness. Acta Ophthalmol. 2014;92 (5):421–425. doi:10.1111/aos.12203 Authorship 12. Sato S, Hirooka K, Nitta E, Ukegawa K, Tsujikawa A. Additive intraocular pressure lowering effects of the , All the authors were involved in the concept and design of ripasudil in glaucoma patients not able to obtain adequate control the study, data acquisition, data analysis and interpretation, after other maximal tolerated medical therapy. Adv Ther. 2016;33 drafting manuscript, technical support and final review of (9):1628–1634. doi:10.1007/s12325-016-0389-3 13. King AJ, Stead RE, Rotchford AP. Treating patients presenting with the manuscript. advanced glaucoma - should we reconsider current practice? Br J Ophthalmol. 2011;95(9):1185–1192. doi:10.1136/bjo.2010.188128 14. Burr J, Azuara-Blanco A, Avenell A. Medical versus surgical inter­ Funding ventions for open angle glaucoma. Cochrane Database Syst Rev. There is no funding to report. 2005;18(2):CD004399. 15. Tanihara H, Inoue T, Yamamoto T, Kuwayama Y, Abe H, Araie M. Phase 1 clinical trials of a selective rho kinase inhibitor, K-115. Disclosure JAMA Ophthalmol. 2013;131(10):1288–1295. doi:10.1001/ jamaophthalmol.2013.323 The authors reported no conflicts of interest for this work. 16. Tanihara H, Inoue T, Yamamoto T, Kuwayama Y, Abe H, Araie M. Phase 2 randomized clinical study of a Rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertension. Am References J Ophthalmol. 2013;156(4):731–6 e732. doi:10.1016/j. 1. Resnikoff S, Pascolini D, Etya D, et al. Global Data on Visual ajo.2013.05.016 Impairment in the Year 2002. Vol. 82. Bulletin of the World Health 17. Tanihara H, Inoue T, Yamamoto T, et al.; K-115 Clinical Study Organization; 2004. Group. One-year clinical evaluation of 0.4% ripasudil (K-115) in 2. Quigley HA, Broman AT. The number of people with glaucoma patients with open-angle glaucoma and ocular hypertension. Acta worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90(3):262–267. Ophthalmol. 2016;94(1):e26–34. doi:10.1111/aos.12829 doi:10.1136/bjo.2005.081224 18. Tanihara H, Inoue T, Yamamoto T, et al. Additive intraocular 3. George R, Ve RS, Vijaya L. Glaucoma in India: estimated burden of pressure-lowering effects of the rho kinase inhibitor ripasudil disease. J Glaucoma. 2010;19(6):391–397. doi:10.1097/ (K-115) combined with timolol or latanoprost: a report of 2 rando­ IJG.0b013e3181c4ac5b mized clinical trials. JAMA Ophthalmol. 2015;133(7):755–761. 4. Gessesse GW, Damji KF. Advanced glaucoma: management pearls. doi:10.1001/jamaophthalmol.2015.0525 Middle East Afr J Ophthalmol. 2013;20(2):131–141. doi:10.4103/ 19. Tanihara H, Inoue T, Yamamoto T, et al.; K-115 Clinical Study 0974-9233.110610 Group. Intra-ocular pressure-lowering effects of a rho kinase inhi­ 5. VanVeldhuisen Paul C, Ederer F. The advanced glaucoma intervention bitor, ripasudil (K-115), over 24 hours in primary open-angle glau­ study (AGIS): 7. The relationship between control of intraocular coma and ocular hypertension: a Randomized, Open-Label, pressure and visual field deterioration. Am J Ophthalmol. Crossover Study. Acta Ophthalmol. 2015;93(4):e254–60. 2000;130:429–440. doi:10.1111/aos.12599

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